TY - JOUR T1 - Differential potency of 2,6 dimethylcyclohexanol isomers for positive modulation of GABAA receptor currents JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.115.228890 SP - jpet.115.228890 AU - Luvana Chowdhury AU - Celine Croft AU - Shikha Goel AU - Naina Zaman AU - Angela Tai AU - Erin M Walch AU - Kelly Smith AU - Alexandra Page AU - Kevin Shea AU - C. Dennis Hall AU - Davit Jishkariani AU - Girinath Pillai AU - Adam C Hall Y1 - 2016/01/01 UR - http://jpet.aspetjournals.org/content/early/2016/03/30/jpet.115.228890.abstract N2 - GABA-A receptors meet all the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6 dimethylcyclohexanol diastereomers were investigated on human γ-aminobutyric acid type A (GABA-A, α1β3γ2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis; trans,trans; and cis,trans isomers were isolated from commercially available 2,6 dimethylcyclohexanol and were tested for positive modulation of sub-maximal GABA responses. For example, the addition of 30 μM cis,cis isomer resulted in ~2-3 fold enhancement of the EC20 GABA current. Co-applications of 30 μM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis > trans,trans ≥ mixture of isomers >> cis,trans isomer. In molecular modeling studies, the three cyclohexanol isomers bound with the highest binding energies to a pocket within transmembrane domains M1 and M2 of the β3 subunit through hydrogen-bonding interactions with a glutamine at the 224 position and a tyrosine at the 220 position. Moreover, the energies for binding to and hydrogen bond lengths within this pocket corresponded with the relative potencies of the agents for positive modulation of GABA-A receptor currents (cis,cis > trans,trans > cis,trans 2,6 dimethylcyclohexanol). In conclusion, the stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABA-A receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices. ER -